Almost a century ago Moreschi and Rous published their separate observations on the impact of caloric restriction (CR) on transplanted and induced tumors. Years later, McCay and colleagues first observed lifespan extension in laboratory rats maintained on a CR diet. Since then, CR has been studied intensively with consistent results showing its beneficial effects on longevity, age-associated diseases, attenuation of functional declines, and carcinogenesis across a variety of species and diet formulations. However, the mechanism(s) underlying the effects of CR protection still remain unknown. Nevertheless, it is safe to say that the three most extensively studied hallmarks of CR are enhanced protection against induced and spontaneous carcinogenesis, reduced insulin/IGF-1 signaling, and increased median and maximum lifespan. Even if CR was shown to benefit human health, confer cancer protection, and increase longevity, it would be extremely difficult to achieve adherence to such a stringent diet that might require a reduction of 20-40% in caloric intake. To this end, considerable investment has been focused on dissecting the pathways that regulate CR benefits that could spur development of pharmacological agents potentially acting as CR mimetics. Several of the currently proposed CR mimetics are phytochemicals (resveratrol, quercetin, and curcumin) that act, at least in part, through the activation of the NF-E2-related factor 2 (Nrf2) pathway. Nrf2 is a transcription factor that binds to the antioxidant response element (ARE) of target genes as an adaptive response to oxidative stress and increases the transcription of a variety of anti-oxidative and carcinogen detoxification enzymes. Stress can result from a variety of causes including fasting, overfeeding, endogenous compounds, exposure to chemicals or environmental agents but generally leads to the production of ROS. As a result of ROS exposure, Nrf2, which is typically bound to Keap1 in the cytoplasm, where it undergoes proteolytic degradation and rapid turnover, is phosphorylated and translocates to the nucleus where it binds to ARE sequences to induce expression of multiple cytoprotective enzymes including NAD(P)H-quinone oxidoreductase 1 (NQO1), glutathione S-transferases (GSTs), and heme oxygenase-1. Mammalian cap 'n' collar transcription factors, such as Nrf2, are thought to be most closely related to the Caenorhabditis elegans gene skn-1. SKN-1 is functionally similar to Nrf2 in that it responds to oxidative stress and up-regulates detoxifying enzymes, and skn-1 mutants have shorter survival and reduced stress response compared with WT worms. The presence of skn-1 in only two neurons is necessary for CR to increase median and maximum lifespan in C. elegans. Because the regulation of lifespan appears dependent on Nrf2-homologous pathways in C. elegans, the survival effects of CR in mammals could be also regulated through Nrf2 transcription factor networks. We have now shown that Nrf2 is responsible for the protection of CR against induced carcinogenesis. However, the lack of Nrf2 did not attenuate lifespan extension or alter the CR improvement on insulin sensitivity in the Nrf2 KO mice. But, it appears now in mammals that besides the involvement of Nrf2 on anti-carcinogenic protection by CR, other factors, perhaps SIRT1, are involved in the regulation of mammalian longevity. We have recently discovered the interaction between these two molecules and we are working on dissecting the physiological and biological meaning of this interaction. Finally and most importantly, this interaction presents itself as a promising target to evaluate preventive strategies against age related diseases and environmentally induced cancers. Recently wee have demonstrated that metformin has a direct effect in the activation of the NRF2 pathway and this effect seems to be sex dependent. Using the strengths of two different strain of mice with different strategies for knocking out NRF2 and fruit flies with different mutations we are trying to dissect the sex specific drivers of this phenotypic differences observed in the mice.